Cardiovascular disease resulting from atherosclerosis is responsible for over half of the deaths in industrialized nations. Lipid abnormalities associated with high serum levels of total cholesterol, LDL cholesterol, and triglyceride greatly increases the likelihood of development of the clinical manifestations of this disease. Examining the novel mechanisms regulating sterol biosynthesis will yield new information on how cells maintain proper sterol homeostasis. Saccharomyces cerevisiae is a model system for the study of sterol regulation. We have discovered a novel transcriptional regulation of sterol gene expression in yeast. We have found that the transcription of the ERG25, ERG26, and ERG27 genes required for the biosynthesis of zymosterol are up regulated in response to sterol accumulation.
The Specific Aims of this application are as follows. (1) Determine whether ERG25, ERG26, and ERG27 are coordinately transcriptionally regulated. We will determine whether ERG25, ERG26, and ERG27 are coordinately regulated in response to various blocks in sterol biosynthesis. We will also determine the mechanism regulating the transcription of these genes with respect to the end product, ergosterol. (2) Determine the promoter sequences required for the sterol-mediated transcriptional regulation of ERG26 gene expression. We will determine the minimal ERG26 promoter sequences required for ERG26 gene expression regulation using ERG26 promoter-lacZ fusion technology. (3) Determine the transcription factors required for the sterol-mediated transcriptional regulation of ERG26 gene expression. We will elucidate the transcription factors required for ERG26 regulation using yeast mutants harboring loss-of-function mutations in known transcription factors and the yeast one-hybrid assay. (4) Determine the role of the yeast oxysterol- binding proteins in the transcriptional regulation of ERG26. Loss-of-function oxysterol-binding protein mutants will be examined for defects in the transcriptional regulation of ERG26. Mutants defective in the yeast Niemann-Pick type C gene will also be examined. (5) Initiate microarray studies that will examine the mechanisms regulating global lipid gene expression. The results of these studies will increase our understanding of the transcriptional mechanisms regulating sterol gene expression in eukaryotes. Moreover, these results may prove useful in the development of new targets for chemotherapeutic intervention with regards to heart disease and Niemann-Pick disease type C.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-SSS-T (01))
Program Officer
Wassef, Momtaz K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Drexel University
Schools of Medicine
United States
Zip Code
Gallo-Ebert, Christina; Donigan, Melissa; Liu, Hsing-Yin et al. (2013) The yeast anaerobic response element AR1b regulates aerobic antifungal drug-dependent sterol gene expression. J Biol Chem 288:35466-77
Gallo-Ebert, Christina; McCourt, Paula C; Donigan, Melissa et al. (2012) Arv1 lipid transporter function is conserved between pathogenic and nonpathogenic fungi. Fungal Genet Biol 49:101-13
Villasmil, Michelle L; Ansbach, Alison; Nickels Jr, Joseph T (2011) The putative lipid transporter, Arv1, is required for activating pheromone-induced MAP kinase signaling in Saccharomyces cerevisiae. Genetics 187:455-65
McCourt, Paula C; Morgan, Jeanelle M; Nickels Jr, Joseph T (2009) Stress-induced ceramide-activated protein phosphatase can compensate for loss of amphiphysin-like activity in Saccharomyces cerevisiae and functions to reinitiate endocytosis. J Biol Chem 284:11930-41
Morgan, Jeanelle; McCourt, Paula; Rankin, Lauren et al. (2009) Altering sphingolipid metabolism in Saccharomyces cerevisiae cells lacking the amphiphysin ortholog Rvs161 reinitiates sugar transporter endocytosis. Eukaryot Cell 8:779-89
Smolock, Elaine M; Wang, Tanchun; Nolt, Jocelyn K et al. (2007) siRNA knock down of casein kinase 2 increases force and cross-bridge cycling rates in vascular smooth muscle. Am J Physiol Cell Physiol 292:C876-85
Fores, Oriol; Arro, Montserrat; Pahissa, Albert et al. (2006) Arabidopsis thaliana expresses two functional isoforms of Arvp, a protein involved in the regulation of cellular lipid homeostasis. Biochim Biophys Acta 1761:725-35
Germann, Melody; Swain, Evelyn; Bergman, Lawrence et al. (2005) Characterizing the sphingolipid signaling pathway that remediates defects associated with loss of the yeast amphiphysin-like orthologs, Rvs161p and Rvs167p. J Biol Chem 280:4270-8
Germann, Melody; Gallo, Christina; Donahue, Timothy et al. (2005) Characterizing sterol defect suppressors uncovers a novel transcriptional signaling pathway regulating zymosterol biosynthesis. J Biol Chem 280:35904-13
Swain, Evelyn; Stukey, Joseph; McDonough, Virginia et al. (2002) Yeast cells lacking the ARV1 gene harbor defects in sphingolipid metabolism. Complementation by human ARV1. J Biol Chem 277:36152-60

Showing the most recent 10 out of 12 publications